Citric acid cycle/ja: Difference between revisions

'''クエン酸サイクル'''（'''Citric acid cycle'''）は、'''Krebs cycle''', '''Szent-Györgyi-Krebs cycle''' '''TCA cycle (tricarboxylic acid cycle)'''とも呼ばれ、 [[carbohydrate/ja|炭水化物]]、[[fat/ja|脂質]]、[[protein/ja|タンパク質]]に由来する[[acetyl-CoA/ja|アセチル-CoA]]の[[Redox|oxidation/ja|酸化還元]]によって[[nutrient/ja|栄養素]]に蓄積されたエネルギーを放出する一連の[[chemical reaction/ja|生化学反応]]である。放出された化学エネルギーは[[Adenosine triphosphate/ja|ATP]]の形で利用できる。[[:en:Hans Krebs (biochemist)|クレブス]]サイクルは、[[anaerobic respiration/ja|嫌気性呼吸]]または[[aerobic respiration/ja|好気性呼吸]]によってエネルギーを生成するために、[[Cellular respiration/ja|呼吸]]を行う[[organism/ja|生物]]（[[Fermentation/ja|発酵]]を行う生物とは異なる）によって使用される。さらに、このサイクルは特定の[[amino acid/ja|アミノ酸]]の[[precursor (chemistry)/ja|前駆体]]、および[[reducing agent/ja|還元剤]]を供給する。[[nicotinamide adenine dinucleotide/ja|NADH]]を供給する。多くの[[Metabolic pathway/ja|生化学的経路]]における中心的な重要性は、それが[[metabolism/ja|代謝]]の最も初期の構成要素の一つであったことを示唆している。クエン酸サイクルは「サイクル」と呼ばれているが、[[metabolite/ja|代謝物]]が1つの特定の経路をたどる必要はない。

クエン酸サイクルは、[[carbohydrate/ja|炭水化物]]、[[fat/ja|脂肪]]、[[protein/ja|タンパク質]]をつなぐ[[metabolic pathwary/ja|代謝経路]]である。このサイクルの[[Chemical reaction/ja|反応]]は8つの[[enzymes/ja|酵素]]によって行われ、[[acetate/ja|酢酸]]（炭素数2の分子）をアセチル-CoAの形で完全に酸化し、それぞれ2分子の二酸化炭素と水にする。糖、脂肪、タンパク質の[[catabolism]/ja|異化]]によって、炭素数2の有機生成物アセチル-CoAが生成され、クエン酸サイクルに入る。サイクルの反応はまた、3当量の[[nicotinamide adenine dinucleotide/ja|ニコチンアミドアデニンジヌクレオチド]]（NAD⁺）を3当量の還元型[[Nicotinamide adenine dinucleotide/ja|NAD⁺]]（NADH）に変換する、 [[flavin adenine dinucleotide/ja|フラビンアデニンジヌクレオチド]]（FAD）を1当量の[[Flavin adenine dinucleotide/ja|FADH₂]]に、[[guanosine diphosphate/ja|グアノシン二リン酸]]（GDP）と無機[[phosphate/ja|リン酸]]（P_i）をそれぞれ1当量の[[guanosine triphosphate/ja|グアノシン三リン酸]]（GTP）に変換する。クエン酸サイクルによって生成されたNADHとFADH₂は、[[oxidative phosphorylation/ja|酸化的リン酸化]]経路によってエネルギー豊富なATPを生成するために使われる。

|不可逆的な段階で[[Nicotinamide adenine dinucleotide/ja|NADH]]を生成 (ATP2.5分）、4C鎖を再生する（CoAは除く）。

Because two acetyl-CoA [[molecules]] are produced from each [[glucose]] molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two [[Flavin adenine dinucleotide|FADH₂]], and four [[Carbon dioxide|CO₂]].

'''Regulation by calcium'''. Calcium is also used as a regulator in the citric acid cycle. Calcium levels in the mitochondrial matrix can reach up to the tens of micromolar levels during cellular activation. It activates [[pyruvate dehydrogenase phosphatase]] which in turn activates the [[pyruvate dehydrogenase complex]]. Calcium also activates [[isocitrate dehydrogenase]] and [[Alpha-ketoglutarate dehydrogenase|α-ketoglutarate dehydrogenase]]. This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway.

'''Transcriptional regulation'''. Recent work has demonstrated an important link between intermediates of the citric acid cycle and the regulation of [[hypoxia-inducible factors]] ([[HIF1A|HIF]]). HIF plays a role in the regulation of oxygen [[homeostasis]], and is a transcription factor that targets [[angiogenesis]], [[Vascular remodelling in the embryo|vascular remodeling]], [[glucose]] utilization, iron transport and [[apoptosis]]. HIF is synthesized constitutively, and [[hydroxylation]] of at least one of two critical [[proline]] residues mediates their interaction with the von Hippel Lindau [[E3 ubiquitin ligase]] complex, which targets them for rapid degradation. This reaction is catalysed by [[prolyl hydroxylase|prolyl 4-hydroxylases]]. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.

<div lang="en" dir="ltr" class="mw-content-ltr">

== Major metabolic pathways converging on the citric acid cycle ==

Several [[catabolic]] pathways converge on the citric acid cycle. Most of these reactions add intermediates to the citric acid cycle, and are therefore known as [[anaplerotic reactions]], from the Greek meaning to "fill up". These increase the amount of acetyl CoA that the cycle is able to carry, increasing the [[Mitochondrion|mitochondrion's]] capability to carry out respiration if this is otherwise a limiting factor. Processes that remove intermediates from the cycle are termed "cataplerotic" reactions.

In this section and in the next, the citric acid cycle intermediates are indicated in ''italics'' to distinguish them from other substrates and end-products.

[[Pyruvate]] molecules produced by [[glycolysis]] are [[active transport|actively transported]] across the inner [[Mitochondrion|mitochondrial]] membrane, and into the matrix. Here they can be [[Redox|oxidized]] and combined with [[coenzyme A]] to form CO₂, ''[[acetyl-CoA]]'', and [[NADH]], as in the normal cycle.

However, it is also possible for pyruvate to be [[carboxylated]] by [[pyruvate carboxylase]] to form ''oxaloacetate''. This latter reaction "fills up" the amount of ''oxaloacetate'' in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle's capacity to metabolize ''acetyl-CoA'' when the tissue's energy needs (e.g. in [[striated muscle tissue|muscle]]) are suddenly increased by activity.

In the citric acid cycle all the intermediates (e.g. ''[[Citric acid|citrate]]'', ''iso-citrate'', ''[[Alpha-Ketoglutaric acid|alpha-ketoglutarate]]'', ''[[Succinic acid|succinate]]'', ''[[Fumaric acid|fumarate]]'', ''[[Malic acid|malate]]'', and ''[[Oxaloacetic acid|oxaloacetate]]'') are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of ''oxaloacetate'' available to combine with ''acetyl-CoA'' to form ''citric acid''. This in turn increases or decreases the rate of [[Adenosine triphosphate|ATP]] production by the mitochondrion, and thus the availability of ATP to the cell.

''[[Acetyl-CoA]]'', on the other hand, derived from pyruvate oxidation, or from the [[beta-oxidation]] of [[fatty acids]], is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of ''acetyl-CoA'' is consumed for every molecule of ''oxaloacetate'' present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of ''acetyl-CoA'' that produces CO₂ and water, with the energy thus released captured in the form of ATP. The three steps of beta-oxidation resemble the steps that occur in the production of oxaloacetate from succinate in the TCA cycle. Acyl-CoA is oxidized to trans-Enoyl-CoA while FAD is reduced to FADH₂, which is similar to the oxidation of succinate to fumarate. Following, [[Trans-2-enoyl-CoA reductase (NADPH)|trans-Enoyl-CoA]] is hydrated across the double bond to beta-hydroxyacyl-CoA, just like fumarate is hydrated to malate. Lastly, beta-hydroxyacyl-CoA is oxidized to beta-ketoacyl-CoA while NAD+ is reduced to NADH, which follows the same process as the oxidation of malate to [[Oxaloacetic acid|oxaloacetate]].

In the liver, the carboxylation of [[cytosol]]ic pyruvate into intra-mitochondrial ''oxaloacetate'' is an early step in the [[gluconeogenesis|gluconeogenic]] pathway which converts [[lactic acid|lactate]] and de-aminated [[alanine]] into glucose, under the influence of high levels of [[glucagon]] and/or [[epinephrine]] in the blood. Here the addition of ''oxaloacetate'' to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (''malate'') is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of [[glycolysis]].

In [[protein catabolism]], [[protein]]s are broken down by [[protease]]s into their constituent amino acids. Their carbon skeletons (i.e. the de-aminated amino acids) may either enter the citric acid cycle as intermediates (e.g. ''alpha-ketoglutarate'' derived from glutamate or glutamine), having an anaplerotic effect on the cycle, or, in the case of [[leucine]], [[isoleucine]], [[lysine]], [[phenylalanine]], [[tryptophan]], and [[tyrosine]], they are converted into ''acetyl-CoA'' which can be burned to CO₂ and water, or used to form [[ketone bodies]], which too can only be burned in tissues other than the liver where they are formed, or excreted via the urine or breath. These latter amino acids are therefore termed "ketogenic" amino acids, whereas those that enter the citric acid cycle as intermediates can only be cataplerotically removed by entering the gluconeogenic pathway via ''malate'' which is transported out of the mitochondrion to be converted into cytosolic oxaloacetate and ultimately into [[glucose]]. These are the so-called "glucogenic" amino acids. De-aminated alanine, cysteine, glycine, serine, and threonine are converted to pyruvate and can consequently either enter the citric acid cycle as ''oxaloacetate'' (an anaplerotic reaction) or as ''acetyl-CoA'' to be disposed of as CO₂ and water.

In [[fat catabolism]], [[triglyceride]]s are [[hydrolysis|hydrolyzed]] to break them into [[fatty acid]]s and [[glycerol]]. In the liver the glycerol can be converted into glucose via [[dihydroxyacetone phosphate]] and [[glyceraldehyde-3-phosphate]] by way of [[gluconeogenesis]]. In skeletal muscle, glycerol is used in [[glycolysis]] by converting glycerol into [[Glycerol 3-phosphate|glycerol-3-phosphate]], then into [[Dihydroxyacetone phosphate|dihydroxyacetone phosphate (DHAP)]], then into glyceraldehyde-3-phosphate.

</div>

In many tissues, especially heart and skeletal [[muscle tissue]], [[fatty acid]]s are broken down through a process known as [[beta oxidation]], which results in the production of mitochondrial ''acetyl-CoA'', which can be used in the citric acid cycle. [[Beta oxidation]] of [[fatty acid]]s with an odd number of [[methylene bridge]]s produces [[propionyl-CoA]], which is then converted into ''[[succinyl-CoA]]'' and fed into the citric acid cycle as an anaplerotic intermediate.

The total energy gained from the complete breakdown of one (six-carbon) molecule of glucose by [[glycolysis]], the formation of 2 ''acetyl-CoA'' molecules, their catabolism in the citric acid cycle, and oxidative phosphorylation equals about 30 [[Adenosine triphosphate|ATP molecules]], in [[eukaryote]]s. The number of ATP molecules derived from the beta oxidation of a 6 carbon segment of a fatty acid chain, and the subsequent [[Redox|oxidation]] of the resulting 3 molecules of [[Acetyl-CoA carboxylase|''acetyl-CoA'' is]] 40.

</div>

<div lang="en" dir="ltr" class="mw-content-ltr">

== Citric acid cycle intermediates serve as substrates for biosynthetic processes ==

In this subheading, as in the previous one, the TCA intermediates are identified by ''italics''.

''Acetyl-CoA'' cannot be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA, ''citrate'' is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. There it is cleaved by [[ATP citrate lyase]] into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as ''malate'' (and then converted back into ''oxaloacetate'' to transfer more ''acetyl-CoA'' out of the mitochondrion). The cytosolic acetyl-CoA is used for [[fatty acid synthesis]] and the [[Mevalonate pathway|production of cholesterol]]. [[Cholesterol]] can, in turn, be used to synthesize the [[Steroid#Steroidogenesis|steroid hormones]], [[Bile acids|bile salts]], and [[vitamin D]].

The carbon skeletons of many [[Essential amino acid|non-essential amino acids]] are made from citric acid cycle intermediates. To turn them into amino acids the [[Keto acid|alpha keto-acids]] formed from the citric acid cycle intermediates have to acquire their amino groups from [[glutamate]] in a [[transamination]] reaction, in which [[Pyridoxine|pyridoxal phosphate]] is a cofactor. In this reaction the glutamate is converted into [[alpha-Ketoglutaric acid|''alpha-ketoglutarate'']], which is a citric acid cycle intermediate. The intermediates that can provide the [[Skeletal formula|carbon skeletons]] for amino acid synthesis are ''[[Oxaloacetic acid|oxaloacetate]]'' which forms [[aspartate]] and [[asparagine]]; and ''alpha-ketoglutarate'' which forms [[glutamine]], [[proline]], and [[arginine]].

Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to form the [[purines]] that are used as the bases in [[DNA]] and [[RNA]], as well as in [[Adenosine triphosphate|ATP]], [[Adenosine monophosphate|AMP]], [[Guanosine triphosphate|GTP]], [[Nicotinamide adenine dinucleotide|NAD]], [[Flavin adenine dinucleotide|FAD]] and [[Coenzyme A|CoA]].

</div>

The [[pyrimidines]] are partly assembled from aspartate (derived from ''oxaloacetate''). The pyrimidines, [[thymine]], [[cytosine]] and [[uracil]], form the complementary bases to the purine bases in DNA and RNA, and are also components of [[Cytidine triphosphate|CTP]], [[Uridine monophosphate|UMP]], [[Uridine diphosphate|UDP]] and [[Uridine triphosphate|UTP]].

The majority of the carbon atoms in the [[porphyrin]]s come from the citric acid cycle intermediate, ''[[succinyl-CoA]]''. These molecules are an important component of the [[hemoprotein]]s, such as [[hemoglobin]], [[myoglobin]] and various [[cytochrome]]s.

During gluconeogenesis [[Gluconeogenesis#Pathway|mitochondrial ''oxaloacetate'' is reduced to ''malate'']] which is then transported out of the mitochondrion, to be oxidized back to oxaloacetate in the cytosol. Cytosolic oxaloacetate is then [[Decarboxylation|decarboxylated]] to [[phosphoenolpyruvate]] by [[phosphoenolpyruvate carboxykinase]], which is the rate limiting step in the conversion of nearly all the [[Glucogenic amino acid|gluconeogenic]] precursors (such as the glucogenic amino acids and lactate) into glucose by the [[liver]] and [[kidney]].

Because the citric acid cycle is involved in both [[catabolic]] and [[anabolic]] processes, it is known as an [[amphibolic]] pathway.

Evan M.W.Duo